2015
Formation of SHY in 2015
Hypothesis of Dr. Hadari
Initial experiments & discovery
2020 publication on bioRxiv
Discovery of SHY pharmacophore & compound library
A bit of history
Mutant forms of the GTPase KRas have long been considered important cancer therapeutic targets. However, measurements from the 1980s suggested that GTP bound to KRas so strongly that it could not be disrupted by small molecule drugs. By 2015, it was widely accepted and reported that KRas was undruggable.
Dr. Hadari believed the 1980s measurements were likely flawed. He founded SHY to test this hypothesis and, if updated measurements supported it, to develop small molecule inhibitors of KRas/GTP binding. Using contemporary measurement techniques, SHY confirmed Dr. Hadari’s hypothesis and concluded that the GTP/KRas interaction should be druggable.
Intentionally pursuing a lean operating model, SHY assembled a team of experienced bench scientists to develop novel assays and to conduct key biological experiments; identified capable collaborators to undertake high-throughput screen and the design and synthesis of its compounds; and assembled an advisory panel of preeminent GTPase scientists.
Through computational analyses of physical and in-silico libraries combined with proprietary high-throughput assays, molecular modeling, and the design and synthesis of optimized derivative chemical structures, SHY has now synthesized hundreds of small molecules that inhibit GTP binding to KRas by competing non-covalently for GTP binding to the KRas GTP binding site. Across the pharmacopeia, the preponderance of drugs interacts with their targets non-covalently – they bind comparatively specifically and are reversible.
SHY’s growing portfolio of patents reflects its leadership in the development of non-covalent GTP/KRas binding modulation.
SHY tests its KRas program molecules in vitro in cell-based assays and in vivo. They demonstrate significant tumor inhibition and good tolerability in mice. SHY anticipates selecting a clinical candidate from its ongoing KRas program in the first half of 2015. This non-covalent, pan-KRas GTP binding inhibitor will differ from currently FDA-approved drugs that target specific KRas mutants covalently outside of the GTP binding site – drugs that unfortunately have proven to lack durable long-term efficacy.
2015
Formation of SHY in 2015
Hypothesis of Dr. Hadari
Initial experiments & discovery
2020 publication on bioRxiv
Discovery of SHY pharmacophore & compound library
Don't be shy!
Partner with us
Explore opportunities to collaborate with SHY
How it all started
Having previously collaborated in the launch for Yale University of an oncology biotech spinoff targeting receptor tyrosine kinases, in 2015, Yaron Hadari, Stan Choy, Michael Schmertzler, and Mark Mitchnick formed SHY to tackle the GTPase KRas. This was an audacious, contrarian objective. KRas mutants are associated with 30% of all human tumors but were then widely accepted to be undruggable.
It is proving it to have been a well-founded and fruitful objective. SHY’s discovery results have expanded to include both GTPase and ATPase targets. In 2025 we expect to select our first in class non-covalent small molecule pan KRas inhibitor competing for GTP binding for clinical development and to file our first IND for a small molecule cancer therapeutic targeting proteasome ATPases. SHY also now has active programs targeting bacterial and fungal infections as well as other underserved diseases.